The present invention relates to optoacoustic imaging employing nanoparticles to enhance detection of objects in a body. The invention has applications that include imaging for medical reasons.
Optoacoustic imaging is to be distinguished from optical imaging. In optical imaging a body is irradiated with light in the visible or infrared wavelength ranges. Transmitted or reflected light in the same ranges is detected to generate images. Optical imaging suffers from the severe disadvantage that resolution of the image is inherently low, because light, whether in the visible or near infrared spectrum, is strongly scattered in the body through interaction with local inhomogeneities.
Optoacoustic methods of imaging rely not on detection of visible or infrared light irradiated onto a body, but on the sensitive detection of ultrasonic waves induced inside the body by optical radiation. Optoacoustic imaging fundamentally is based on the optical properties of the tissue it detects, but it relies on the sensitive detection of induced ultrasonic waves rather than light itself for image generation. Its resolution is like that of an ultrasound image rather than that of an optical image. Optoacoustic imaging (Oraevsky et al., U.S. Pat. No. 5,840,023) is the use of lasers to generate light of a narrow spectrum or specific wavelengths to irradiate the tissue to be examined, a so-called laser optoacoustic imaging system (“LOIS”). The principle of the LOIS system is that the preferential absorption of short laser pulses of irradiation by tissues containing an absorbing chromophore, such as hemoglobin in blood-rich cancerous tumors, generates pressure disturbances centered on the absorption sites. The rapid increase of the local pressure at the absorption sites leads to pressure pulse propagating through the bulk of the tissue according to the rules of sound transmission. The shapes of the pressure waves retain information about the shapes of the regions of origin (Oraevsky, 1993; Diebold, 1994).
The term “optoacoustic imaging” as used herein applies to any imaging method in which electromagnetic radiation generates a detectable pressure wave or sound from which an image is calculated. Optoacoustic imaging is equivalent in meaning to the term, “photoacoustic imaging,” used by others to refer to the same technology. However, the term “optoacoustic” is not universally so used, and indeed has been combined with the word “imaging” by Unger and Wu in U.S. Pat. No. 6,123,923 to describe a different imaging technology (light irradiation of their method plays no role in the generation of a detected acoustic signal). As used herein, the term “optoacoustic imaging” as used by Unger and Wu in U.S. Pat. No. 6,123,923 has no relevance to light irradiated optoacoustic imaging.
To those uninitiated in this art, it may be surprising that it is possible to generate sound from light with high efficiency. In fact, optoacoustic imaging is quite sensitive as an imaging method. The temperature increase produced by the absorption of the light energy that is necessary to produce the detected signal is only a small fraction of a temperature degree. Nevertheless, the pressure generated by this local temperature increase generates a readily detectable acoustic wave. Recent advances in optoacoustic imaging have allowed the visualization, quantitative characterization and real-time monitoring in the depth of human tissue with sensitivity and resolution superior to that of pure optical methods (Oraevsky et al. in U.S. Pat. Nos. 5,840,023, 6,405,069, and 6,498,942). Some of these advances have come through the use of contrast agents for optoacoustic imaging, as was anticipated by Oraevsky et al. in U.S. Pat. No. 5,840,023 and was taught specifically for both soluble and insoluble contrast agents by Henrichs et al. in U.S. Pat. No. 6,662,040 and PCT publication W09857667. Subsequently, other inventors have taught the use of specific classes of soluble contrast agents for optoacoustic imaging (U.S. Pat. Nos. 6,180,085; 6,180,087; 6,183,726; 6,190,641; 6,264,920; 6,264,919; and 6,395,257; and in U.S. Patent Application 20020044909, now U.S. Pat. No. 6,641,798).
Unlike optical imaging, the diffusion of light by the tissues produced by strong light scattering is not a problem for optoacoustic imaging. Indeed, light diffusion actually helps to bathe the interior of the tissues uniformly with the radiation. Furthermore, the extent to which an internal tissue component, such as a cancerous tumor, absorbs light is enhanced by the presence of scattering centers within that component. These centers lengthen the effective path length followed by a photon in passing through the tissue component. Thus, the chance that the photon will be absorbed by tissue molecular constituents is increased. It is the ultrasound produced by the absorption of the light that provides the information necessary for image calculation. Thus, the resolution of optoacoustic imaging is closer to that for ultrasound imaging than it is to that for optical imaging. Nevertheless, optoacoustic imaging retains the high contrast of pure optical imaging. It has the best features of both optical and ultrasound imaging.
Recent advances have greatly enhanced the ability of optical imaging, especially with near-infrared radiation, to show features in the human breast and other organs. There have been a number of patents describing novel contrast agents and novel uses of contrast agents with respect to optical imaging. Licha et al. teach the use of colloidal dye suspensions for optical imaging (U.S. Pat. App. 2002022004). Some of the inventors of contrast agents for optical imaging have recognized that particulate contrast agents will have utility. For example, Klaveness et al. teach the use of particulate contrast agents, which may or may not comprise a light-absorbing component, in optical imaging (Eur. Pat. EP0808175). Particulate materials are well known as contrast agents for X-ray (and ultrasound) imaging. (Encapsulated gas bubbles form the most significant class of contrast agents for ultrasonic imaging.) There is a long series of patents relating to the stabilization of nanoparticles in X-ray contrast agents (U.S. Pat. Nos. 5,472,683, 5,500,204, 5,521,218, 5,525,328, 5,543,133, 5,447,710, 5,560,932, 5,573,783, 5,580,579, 6,270,806 and Eur. Pat. Nos. EP0601618 and EP0602700). West et al. describe the preparation of nanoshells comprising a particle core covered with a metal shell have optical properties that can make them useful as contrast agents for optical imaging (U.S. Pat. Nos. 6,344,272, 6,438,811, U.S. Pat. App. Publication No. 20020160195, now U.S. Pat. No. 6,660,381, U.S. Pat. App. Publication Nos. 20010002275 and 20020132045, and PCT WO0106257 and PCT WO02059226). They also describe the use of nanoshells of arbitrary shape as contrast agents in optical imaging (U.S. Pat. App. Publication No. 2002013517, now U.S. Pat. No. 6,530,944).
There would be real benefit in having a light based detection system that can detect objects as small as 1 mm. Imaging resolution on the order of 1 mm is necessary for tumor detection at a stage when it is readily treatable. The general wisdom is that smaller size tumors will be easier to cure. There is a significant medical need for imaging methods that boost both sensitivity and resolution to about 1 mm or smaller. Greater sensitivity will allow the detection of both smaller tumors and tumors that have reduced blood content because they are in an early stage of development or because of therapeutic interventions. Tumors in the prostate or breast or in other organs at such an early stage of development may be termed “nascent tumors.” Nascent tumors differ from precancerous lesions in they contain identifiable cancerous cells. However, they have not yet developed into recognizable tumor masses. In particular, they have not yet developed the extensive vascular network that is characteristic of many larger solid tumors. For detection of nascent cancerous tumors, it may no longer be sufficient to rely on differences in the blood content and normal tissue. The blood content of a nascent cancerous tumor is likely to be similar to that of normal tissue. An alternative detection strategy will be required. Currently, however, neither pure optical imaging can nor prior optoacoustic imaging could detect tumors as small as 1 mm. It is unlikely that images of the interior of the human breast or any other thick part of the body will ever be produced by pure optical imaging with a resolution of about 1 mm.
Other than detection of cancers, near infrared optoacoustic imaging has important other advantages, as will be further detailed below in describing various embodiments of our invention.